Characterizing the influence of cardiorespiratory fitness on left atrial size and function in the general population.

Increased left atrial (LA) size and reduced LA function have been associated with heart failure and atrial fibrillation (AF) in at-risk populations. However, atrial remodeling has also been associated with exercise training and the relationship between fitness, LA size, and function has not been defined across the fitness spectrum. In a cross-sectional study of 559 ostensibly healthy participants, comprising 304 males (mean age, 46 ± 20 yr) and 255 females (mean age, 47 ± 15 yr), we sought to define the relationship between cardiorespiratory fitness (CRF), LA size, and function. We also aimed to interrogate sex differences in atrial factors influencing CRF. Echocardiographic measures included biplane measures of LA volumes indexed to body surface area (LAVi) and atrial deformation using two-dimensional speckle tracking. CRF was measured as peak oxygen consumption (V̇o2peak) during cardiopulmonary exercise testing (CPET). Using multivariable regression, age, sex, weight, and LAVi (P < 0.001 for all) predicted V̇o2peak (P < 0.001, R2 = 0.66 for combined model). After accounting for these variables, heart rate reserve added strength to the model (P < 0.001, R2 = 0.74) but LA strain parameters did not predict V̇o2peak. These findings add important nuance to the perception that LA size is a marker of cardiac pathology. LA size should be considered in the context of fitness, and it is likely that the adverse prognostic associations of increased LA size may be confined to those with LA enlargement and low fitness.NEW & NOTEWORTHY Left atrial (LA) structure better predicts cardiorespiratory fitness (CRF) than LA function. LA function adds little statistical value to predictive models of peak oxygen uptake (V̇o2peak) in healthy individuals, suggesting limited discriminatory for CRF once LA size is factored. In the wider population of ostensibly healthy individuals, the association between increased LA volume and higher CRF provides an important counter to the association between atrial enlargement and heart failure symptoms in those with cardiac pathology.

Use of Clinical and Echocardiographic Evaluation to Assess the Risk of Heart Failure.

BACKGROUND: Clinical and echocardiographic features predict incident heart failure (HF), but the optimal strategy for combining them is unclear. OBJECTIVES: This study sought to define an effective means of using echocardiography in HF risk evaluation. METHODS: The same clinical and echocardiographic evaluation was obtained in 2 groups with HF risk factors: a training group (n = 926, followed to 7 years) and a validation group (n = 355, followed to 10 years). Clinical risk was categorized as low, intermediate, and high using 4-year ARIC (Atherosclerosis Risk In Communities) HF risk score cutpoints of 9% and 33%. A risk stratification algorithm based on clinical risk and echocardiographic markers of stage B HF (SBHF) (abnormal global longitudinal strain [GLS], diastolic dysfunction, or left ventricular hypertrophy) was developed using a classification and regression tree analysis and was validated. RESULTS: HF developed in 12% of the training group, including 9%, 18%, and 73% of low-, intermediate-, and high-risk patients. HF occurred in 8.6% of stage A HF and 19.4% of SBHF (P < 0.001), but stage A HF with clinical risk of ≥9% had similar outcome to SBHF. Abnormal GLS (HR: 2.92 [95% CI: 1.95-4.37]; P < 0.001) was the strongest independent predictor of HF. Normal GLS and diastolic function reclassified 61% of the intermediate-risk group into the low-risk group (HF incidence: 12%). In the validation group, 11% developed HF over 4.5 years; 4%, 17%, and 39% of low-, intermediate-, and high-risk groups. Similar results were obtained after exclusion of patients with known coronary artery disease. The echocardiographic parameters also provided significant incremental value to the ARIC score in predicting new HF admission (C-statistic: 0.78 [95% CI: 0.71-0.84] vs 0.83 [95% CI: 0.77-0.88]; P = 0.027). CONCLUSIONS: Clinical risk assessment is adequate to classify low and high HF risk. Echocardiographic evaluation reclassifies 61% of intermediate-risk patients.

Associations between symptoms and functional capacity in patients after COVID-19 infection and community controls.

BACKGROUND: Post-acute sequelae of COVID-19 (PASC or 'long COVID') reflect ongoing symptoms, but these are non-specific and common in the wider community. Few reports of PASC have been compared with a control group. AIMS: To compare symptoms and objective impairment of functional capacity in patients with previous COVID-19 infection with uninfected community controls. METHODS: In this community-based, cross-sectional study of functional capacity, 562 patients from Western Melbourne who had recovered from COVID-19 infections in 2021 and 2022 were compared with controls from the same community and tested for functional capacity pre-COVID-19. Functional impairment (<85% of the predicted response) was assessed using the Duke Activity Status Index (DASI) and 6-min walk distance (6MWD) test. A subgroup underwent cardiopulmonary exercise testing before and after exercise training. RESULTS: Of 562 respondents (age 54 ± 12 years, 69% women), 389 were symptomatic. Functional impairment (<85% predicted metabolic equivalent of tasks) was documented by DASI in 149 participants (27%), and abnormal 6MWD (<85% predicted) was observed in 14% of the symptomatic participants. Despite fewer risk factors and younger age, patients with COVID-19 had lower functional capacity by 6MWD (P < 0.001) and more depression (P < 0.001) than controls. In a pilot group of seven participants (age 58 ± 12 years, two women, VO2 18.9 ± 5.7 mL/kg/min), repeat testing after exercise training showed a 20% increase in peak workload. CONCLUSIONS: Although most participants (69%) had symptoms consistent with long COVID, significant subjective functional impairment was documented in 27% and objective functional impairment in 14%. An exercise training programme might be beneficial for appropriately selected patients.

Measurement of Stroke Volume With Echocardiography Compared to Gold Standard Cardiac Magnetic Resonance Imaging: An Observational Study.

OBJECTIVES: The authors aimed to compare the assessment of left ventricular (LV) stroke volume with transthoracic echocardiography (TTE) using 2- and 3-dimensional (2D and 3D) Doppler and volumetric techniques with gold standard cardiac magnetic resonance imaging (CMR). DESIGN: An observational study. SETTING: A medical research institute. PARTICIPANTS: A total of 187 volunteer participants free of known structural heart disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: LV stroke volume was measured with TTE using the following 4 techniques: LV outflow tract (LVOT) pulsed wave Doppler with 2D LVOT area, LVOT pulsed wave Doppler with 3D LVOT area, 2D volumetric (Simpson's biplane), and 3D volumetric techniques. This was compared with gold standard CMR. Stroke volume measured with echocardiography underestimated stroke volume compared to CMR by all techniques (p < 0.001 for all values compared to CMR). The LVOT Doppler stroke volume with a 3D area most closely agreed with CMR, with a bias of 6.35%. This bias progressively increased with 3D volumetric (13.4%), LVOT Doppler with a 2D area (15.1%), and 2D volumetric (18.3%) stroke volume techniques, with wider limits of agreement. CONCLUSION: Of the 4 echocardiographic LV stroke volume measurement methods the authors assessed, stroke volume with LVOT Doppler using 3D measurement of LVOT area most closely approximates gold standard CMR.

Too Little of a Good Thing: Strong Associations Between Cardiac Size and Fitness Among Women.

BACKGROUND: Cardiorespiratory fitness (CRF) is associated with functional impairment and cardiac events, particularly heart failure (HF). However, the factors predisposing women to low CRF and HF remain unclear. OBJECTIVES: This study sought to evaluate the association between CRF and measures of ventricular size and function and to examine the potential mechanism linking these factors. METHODS: A total of 185 healthy women aged >30 years (51 ± 9 years) underwent assessment of CRF (peak volume of oxygen uptake [Vo2peak]) and biventricular volumes at rest and during exercise by using cardiac magnetic resonance (CMR). The relationships among Vo2peak, cardiac volumes, and echocardiographic measures of systolic and diastolic function were assessed using linear regression. The effect of cardiac size on cardiac reserve (change in cardiac function during exercise) was assessed by comparing quartiles of resting left ventricular end-diastolic volume (LVEDV). RESULTS: Vo2peak was strongly associated with resting measures of LVEDV and right ventricular end-diastolic volume (R2 = 0.58-0.63; P < 0.0001), but weakly associated with measures of resting left ventricular (LV) systolic and diastolic function (R2 = 0.01-0.06; P < 0.05). Increasing LVEDV quartiles were positively associated with cardiac reserve, with the smallest quartile showing the smallest reduction in LV end-systolic volume (quartile [Q]1: -4 mL vs Q4: -12 mL), smallest augmentation in LV stroke volume (Q1: +11 mL vs Q4: +20 mL) and cardiac output (Q1: +6.6 L/min vs Q4: +10.3 L/min) during exercise (interaction P < 0.001 for all). CONCLUSIONS: A small ventricle is strongly associated with low CRF because of the combined effect of a smaller resting stroke volume and an attenuated capacity to increase with exercise. The prognostic implications of low CRF in midlife highlight the need for further longitudinal studies to determine whether women with small ventricles are predisposed to functional impairment, exertional intolerance, and HF later in life.

Current Applications of Robot-Assisted Ultrasound Examination.

Despite advances in miniaturization and automation, the need for expert acquisition of a full echocardiogram, including Doppler, has restricted access in remote areas. Recent developments in robotics, teleoperation, and upgraded telecommunications infrastructure may provide a solution to this deficiency. Robot-assisted teleoperated ultrasound examination can aid medical diagnosis in remote locations and may improve health inequalities between rural and urban settings. This review aimed to analyze the status of teleoperated robotic systems for ultrasound examinations, evaluate clinical and preclinical applications, identify limitations, and outline future directions for clinical use. Overall, robot-assisted teleoperated ultrasound is feasible and safe in the reported clinical and preclinical studies, with the robots able to follow the hand movements performed by sonographers and researchers from a distance or in local networks. Moreover, multiple types of ultrasound examinations have been performed in remote areas, with a high success rate nearly comparable to that of conventional sonography. The studies showed that although a low-bandwidth link can be used to control a robot, the bandwidth requirements for real-time transmission of video and ultrasound images are significantly higher. Furthermore, if haptic feedback is implemented, the bandwidth requirements are increased. Haptically enabled systems that improve robotic control are necessary for accelerating the introduction to clinical use. Haptic feedback and enhanced front-end interface control for remote users are vital aspects required for clinical application. The incorporation of artificial intelligence through either aiding in window acquisition (knowledge of anatomical landmarks to adjust scanning planes) or through measurement and disease identification is yet to be researched. However, it has the potential to lead to dramatic advances. A new generation of robots is in development, and several projects in the preclinical stage reveal a promising future to overcome the shortage of health professionals in remote areas.

Echocardiographic detection of heart valve disease in a community cohort of asymptomatic Australians > 65 years with cardiovascular risk factors.

BACKGROUND: Valvular heart disease is becoming an increasingly prevalent with population ageing. We sought to define the current prevalence of valvular heart disease in Australia. METHODS: The TasELF and VicELF studies prospectively recruited 962 asymptomatic participants ≥65 years, with at least one cardiovascular risk factor, from the Tasmanian and Victorian communities. People were excluded if they had a previous diagnosis of heart failure, or a life expectancy <1 year. All underwent baseline echocardiography. Those with moderate or severe valvular disease were identified. The current prevalence of clinically significant valve disease was applied to the Australian Bureau of Statistics population projections. RESULTS: Echocardiograms were interpretable in 943 participants (98%). Clinically significant valve disease was present in 5% of the population, and mitral regurgitation was the most common overall valvular lesion, present in 36% of the population. The projected numbers of people with clinically significant valvular disease is expected to increase significantly across all age groups by the year 2060. CONCLUSIONS: Clinically significant yet asymptomatic valvular disease was prevalent in a large community cohort of participants with at least one risk factor. The total burden of valvular heart disease is expected to increase dramatically over the coming decades.

Exercise for the Prevention of Anthracycline-Induced Functional Disability and Cardiac Dysfunction: The BREXIT Study.

BACKGROUND: Breast cancer survivors treated with anthracycline-based chemotherapy (AC) have increased risk of functional limitation and cardiac dysfunction. We conducted a 12-month randomized controlled trial in 104 patients with early-stage breast cancer scheduled for AC to determine whether 12 months of exercise training (ExT) could attenuate functional disability (primary end point), improve cardiorespiratory fitness (VO2peak), and prevent cardiac dysfunction. METHODS: Women 40 to 75 years of age with stage I to III breast cancer scheduled for AC were randomized to 3 to 4 days per week aerobic and resistance ExT for 12 months (n=52) or usual care (UC; n=52). Functional measures were performed at baseline, at 4 weeks after AC (4 months), and at 12 months, comprising: (1) cardiopulmonary exercise testing to quantify VO2peak and functional disability (VO2peak ≤18.0 mL·kg-1·min-1); (2) cardiac reserve (response from rest to peak exercise), quantified with exercise cardiac magnetic resonance measures to determine changes in left and right ventricular ejection fraction, cardiac output, and stroke volume; (3) standard-of-care echocardiography-derived resting left ventricular ejection fraction and global longitudinal strain; and (4) biochemistry (troponin and BNP [B-type natriuretic peptide]). RESULTS: Among 104 participants randomized, greater study attrition was observed among UC participants (P=0.031), with 93 women assessed at 4 months (ExT, n=49; UC, n=44) and 87 women assessed at 12 months (ExT, n=49; UC, n=38). ExT attenuated functional disability at 4 months (odds ratio, 0.32 [95% CI, 0.11-0.94]; P=0.03) but not at 12 months (odds ratio, 0.27 [95% CI, 0.06-1.12]; P=0.07). In a per-protocol analysis, functional disability was prevented entirely at 12 months among participants adherent to ExT (ExT, 0% versus UC, 20%; P=0.005). Compared with UC at 12 months, ExT was associated with a net 3.5-mL·kg-1·min-1 improvement in VO2peak that coincided with greater cardiac output, stroke volume, and left and right ventricular ejection fraction reserve (P<0.001 for all). There was no effect of ExT on resting measures of left ventricular function. Postchemotherapy troponin increased less in ExT than in UC (8-fold versus 16-fold increase; P=0.002). There were no changes in BNP in either group. CONCLUSIONS: In women with early-stage breast cancer undergoing AC, 12 months of ExT did not attenuate functional disability, but provided large, clinically meaningful benefits on VO2peak and cardiac reserve. REGISTRATION: URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12617001408370.

A membrane-free microfluidic approach to mucus permeation for efficient differentiation of mucoadhesive and mucopermeating nanoparticulate systems.

The gastrointestinal mucus barrier is a widely overlooked yet essential component of the intestinal epithelium, responsible for the body's protection against harmful pathogens and particulates. This, coupled with the increasing utilisation of biological molecules as therapeutics (e.g. monoclonal antibodies, RNA vaccines and synthetic proteins) and nanoparticle formulations for drug delivery, necessitates that we consider the additional absorption barrier that the mucus layer may pose. It is imperative that in vitro permeability methods can accurately model this barrier in addition to standardised cellular testing. In this study, a mucus-on-a-chip (MOAC) microfluidic device was engineered and developed to quantify the permeation kinetics of nanoparticles through a biorelevant synthetic mucus layer. Three equivalently sized nanoparticle systems, formulated from chitosan (CSNP), mesoporous silica (MSNP) and poly (lactic-co-glycolic) acid (PLGA-NP) were prepared to encompass various surface chemistries and nanostructures and were assessed for their mucopermeation within the MOAC. Utilising this device, the mucoadhesive behaviour of chitosan nanoparticles was clearly visualised, a phenomenon not often observed via standard permeation models. In contrast, MSNP and PLGA-NP displayed mucopermeation, with significant differences in permeation pattern due to specific mucus-nanoparticle binding. Further optimisation of the MOAC to include a more biorelevant mucus mimic resulted in 5.5-fold hindered PLGA-NP permeation compared to a mucin solution. Furthermore, tracking of PLGA-NP at a single nanoparticle resolution revealed rank-order correlations between particle diffusivity and MOAC permeation. This device, including utilisation of biosimilar mucus, provides a unique ability to quantify both mucoadhesion and mucopenetration of nano-formulations and elucidate mucus binding interactions on a microscopic scale.

Three-dimensional echocardiography of the athlete's heart: a comparison with cardiac magnetic resonance imaging.

Three-dimensional echocardiography (3DE) is the most accurate cardiac ultrasound technique to assess cardiac structure. 3DE has shown close correlation with cardiac magnetic resonance imaging (CMR) in various populations. There is limited data on the accuracy of 3DE in athletes and its value in detecting alterations during follow-up. Indexed left and right ventricular end-diastolic volume (LVEDVi, RVEDVi), end-systolic volume, ejection fraction (LVEF, RVEF) and left ventricular mass (LVMi) were assessed by 3DE and CMR in two-hundred and one competitive endurance athletes (79% male) from the Pro@Heart trial. Sixty-four athletes were assessed at 2 year follow-up. Linear regression and Bland-Altman analyses compared 3DE and CMR at baseline and follow-up. Interquartile analysis evaluated the agreement as cardiac volumes and mass increase. 3DE showed strong correlation with CMR (LVEDVi r = 0.91, LVEF r = 0.85, LVMi r = 0.84, RVEDVi r = 0.84, RVEF r = 0.86 p < 0.001). At follow up, the percentage change by 3DE and CMR were similar (∆LVEDVi r = 0.96 bias - 0.3%, ∆LVEF r = 0.94, bias 0.7%, ∆LVMi r = 0.94 bias 0.8%, ∆RVESVi r = 0.93, bias 1.2%, ∆RVEF r = 0.87 bias 0.4%). 3DE underestimated volumes (LVEDVi bias - 18.5 mL/m2, RVEDVi bias - 25.5 mL/m2) and the degree of underestimation increased with larger dimensions (Q1vsQ4 LVEDVi relative bias - 14.5 versus - 17.4%, p = 0.016; Q1vsQ4 RVEDVi relative bias - 17 versus - 21.9%, p = 0.005). Measurements of cardiac volumes, mass and function by 3DE correlate well with CMR and 3DE accurately detects changes over time. 3DE underestimates volumes and the relative bias increases with larger cardiac size.

Mimicking the Gastrointestinal Mucus Barrier: Laboratory-Based Approaches to Facilitate an Enhanced Understanding of Mucus Permeation.

The gastrointestinal mucus layer plays a significant role in maintaining gut homeostasis and health, offering protective capacities against the absorption of harmful pathogens as well as commensal gut bacteria and buffering stomach acid to protect the underlying epithelium. Despite this, the mucus barrier is often overlooked during preclinical pharmaceutical development and may pose a significant absorption barrier to high molecular weight or lipophilic drug species. The complex chemical and physical nature of the dynamic mucus layer has proven problematic to reliably replicate in a laboratory setting, leading to the development of multiple mucus models with varying complexity and predictive capacity. This, coupled with the wide range of analysis methods available, has led to a plethora of possible approaches to quantifying mucus permeation; however, the field remains significantly under-represented in biomedical research. For this reason, the development of a concise collation of the available approaches to mucus permeation is essential. In this review, we explore widely utilized mucus mimics ranging in complexity from simple mucin solutions to native mucus preparations for their predictive capacity in mucus permeation analysis. Furthermore, we highlight the diverse range of laboratory-based models available for the analysis of mucus interaction and permeability with a specific focus on in vitro, ex vivo, and in situ models. Finally, we highlight the predictive capacity of these models in correlation with in vivo pharmacokinetic data. This review provides a comprehensive and critical overview of the available technologies to analyze mucus permeation, facilitating the efficient selection of appropriate tools for further advancement in oral drug delivery.

Optimisation of a High-Throughput Model for Mucus Permeation and Nanoparticle Discrimination Using Biosimilar Mucus.

High-throughput permeation models are essential in drug development for timely screening of new drug and formulation candidates. Nevertheless, many current permeability assays fail to account for the presence of the gastrointestinal mucus layer. In this study, an optimised high-throughput mucus permeation model was developed employing a highly biorelevant mucus mimic. While mucus permeation is primarily conducted in a simple mucin solution, the complex chemistry, nanostructure and rheology of mucus is more accurately modelled by a synthetic biosimilar mucus (BSM) employing additional protein, lipid and rheology-modifying polymer components. Utilising BSM, equivalent permeation of various molecular weight fluorescein isothiocyanate-dextrans were observed, compared with native porcine jejunal mucus, confirming replication of the natural mucus permeation barrier. Furthermore, utilising synthetic BSM facilitated the analysis of free protein permeation which could not be quantified in native mucus due to concurrent proteolytic degradation. Additionally, BSM could differentiate between the permeation of poly (lactic-co-glycolic) acid nanoparticles (PLGA-NP) with varying surface chemistries (cationic, anionic and PEGylated), PEG coating density and size, which could not be achieved by a 5% mucin solution. This work confirms the importance of utilising highly biorelevant mucus mimics in permeation studies, and further development will provide an optimal method for high-throughput mucus permeation analysis.

Association of biomarkers and risk scores with subclinical left ventricular dysfunction in patients with type 2 diabetes mellitus.

BACKGROUND: Subclinical LV dysfunction (LVD) identifies heart failure (HF) risk in type 2 diabetes mellitus (T2DM). We sought the extent to which clinical scores (ARIC-HF, WATCH-DM), natriuretic peptides (NTpBNP) and troponin (hs-TnT) were associated with subclinical LV dysfunction (LVD). These associations could inform the ability of these tests to identify which patients should undergo echocardiography. METHODS: Participants with T2DM were prospectively recruited from three community-based populations. ARIC-HF risk at 4 years and WATCH-DM scores were calculated from clinical data. NTpBNP and hs-TnT were measured using an electro-chemiluminescence assay. All underwent a comprehensive echocardiogram. We calculated the sensitivity and specificity of clinical scores and biomarkers to identify abnormal global longitudinal strain (GLS ≥ -16%)), diastolic function (E/e' ≥ 14 or e' < 8 cm/s), left atrial volume index (LAV > 34 ml/m2) and LV hypertrophy (LV mass index > 88 g/m2 (F) > 102 g/m2(M)). RESULTS: Of 804 participants (median age 69 years [inter-quartile range (IQR) 65-73], 36% female), clinical scores suggested significant HF risk (median ARIC-HF 8% [IQR 4-12]; WATCH-DM 10 points [IQR 8-12]), and the median NTpBNP was 50 pg/mL [IQR 25-101] and hs-TnT 9.6 pg/mL [IQR 6.8-13.6]. Abnormal GLS was present in 126 (17%), elevated E/e' in 114 (15%), impaired e' in 629 (78%), increased LAV in 351 (44%) and LV hypertrophy in 113 (14%). After adjustments for age, body-mass index, and renal function, each standard deviation increase in NTpBNP was associated with a GLS increase of 0.32 (p < 0.001) and hs-TnT increase by 0.26 (p < 0.001). Similar trends were observed with ARIC-HF (standardised ß = 0.22, p < 0.001) and WATCH-DM (standardised ß = 0.22, p < 0.001) in univariable analyses. However, none of the risk assessment tools provided satisfactory discrimination for abnormal GLS (AUC 63%), diastolic indices (e' AUC 54-61%) or LV mass (AUC 59-67%). At a sensitivity of 90%, there was an unacceptably low (< 50%) specificity. CONCLUSION: Although risk assessment based on clinical scores or biomarkers would be desirable to stratify HF risk in people with T2DM, they show a weak relationship with subclinical LVD.

Diastolic flow in the left ventricular outflow tract - A normal physiological and underappreciated echocardiographic finding.

Purpose: Diastolic waveforms in the left ventricular outflow tract (LVOT) are commonly observed with Doppler echocardiography. The incidence and mechanism are not well described. Methods: This was a retrospective observational study of 186 adult patients, athletes and non-athletes, free of known cardiac disease, presenting for comprehensive transthoracic echocardiography at a research institute. We aimed to evaluate the incidence and echocardiographic associations between LVOT diastolic waveforms. Results: Left ventricular outflow tract early to mid-diastolic waveforms were present in 100% of athletes and 95% of non-athletes. The LVOT diastolic velocity time integral was larger in athletes than non-athletes with a mean 8.3 cm (95% CI (7.6-8.9)) vs. 5.1 cm (4.4-5.9) (P < 0.0001). Multivariate predictors of this diastolic waveform were age (P = 0.002), slower heart rate (P = 0.035), higher stroke volume (P = 0.003), large mitral E (P = 0.019) and higher E/e' (P = 0.015). Discussion: An LVOT early diastolic wave is a normal physiological finding. It is related to a flow vortex redirecting diastolic mitral inflow around anterior mitral valve leaflet into the LVOT. Conclusions: Early to mid-diastolic LVOT waves are present in almost all patients but more prominent in young athletes than non-athletes. Diastolic LVOT waves increase with younger age, slower heart rate, larger stroke volume and enhanced diastolic function.

Nurse-Provided Lung and Inferior Vena Cava Assessment in Patients With Heart Failure.

BACKGROUND: Residual congestion detected using handheld ultrasound may be associated with increased risk of readmission and death after hospitalization for acute decompensated heart failure (ADHF). However, effective application necessitates routine use by nonexperts delivering clinical care. OBJECTIVES: The objective of this study was to determine the ability of heart failure (HF) nurses to deliver a predischarge lung and inferior vena cava (IVC) assessment (LUICA) to predict 90-day outcomes. METHODS: In this multisite, prospective, observational study, HF nurses scanned 240 patients with ADHF (median age: 77 years; 56% men) using a 9-zone LUICA protocol. Obtained images were reviewed by independent nurses who were blinded to clinical characteristics and outcomes. Based on a B-line cut-off of 10, patients were dichotomized as congested (n = 115) or not congested (n = 125). RESULTS: Congested patients were more likely to have previous cardiac operations, long-standing HF (>6 months), and renal impairment. At 90 days, HF readmission or mortality occurred in 42 congested patients (37%) compared with 18 noncongested patients (14%). Pulmonary congestion increased at 30-day (OR: 3.86; 95% CI: 1.65-8.99; P < 0.01) and 90-day (OR: 3.42; 95% CI: 1.82-6.4; P < 0.01) HF readmission or mortality risk and 90-day mortality (OR: 5.18; 95% CI: 1.44-18.69; P < 0.01). Pulmonary congestion increased the 90-day odds of HF readmission and/or death by 3.3- to 4.2-fold (P < 0.01), independent of demographics, HF characteristics, comorbidities, and event risk score. Over 90 days, days alive out of hospital were fewer (78.3 ± 21.4 days vs 85.5 ± 12.4 days; P < 0.01) in congested patients. CONCLUSIONS: LUICA can be a powerful tool for detection of predischarge residual congestion. HF nurses can obtain images and provide diagnostic reports that are predictive of ADHF outcomes.

Quantification of cardiac and respiratory modulation of axonal activity in the human vagus nerve.

We recently documented the first microelectrode recordings from the cervical vagus nerve in awake humans. Here we aimed to quantify cardiac and respiratory modulation of vagal activity to assess the feasibility of targeting axons supplying the heart and airways. Multi-unit activity was recorded from 43 sites in 19 healthy participants in the left (n = 10) and right (n = 9) vagus nerves with ECG, continuous non-invasive blood pressure and respiration. Cross-correlation histograms were constructed between axonal spikes and the R-waves or the peaks of inspiration. The latencies for the peak in cardiac modulation showed a bimodal distribution: while the majority of sites (72%) had peak latencies that preceded the R-wave by up to 550 ms (mean ± SD, -300 ± 178 ms), 12 sites had latencies of up to 250 ms following the R-wave (64 ± 87 ms). Interestingly, the majority of sites with negative latencies (68%) were found in the left nerve whereas most of those with positive latencies (75%) were found in the right. Conversely, on average the peak of respiratory modulation straddled the peak of inspiration. Sites showing respiratory modulation were more prevalent and showed stronger modulation than those with cardiac modulation: calculated for sites with modulation indices ≥15%, the median cardiac and respiratory modulation indices were 23.4% (n = 17) and 44.5% (n = 35), respectively. We conclude that, despite the fact that much of the vagus nerve supplies the gut, cardiac and respiratory modulation of vagal nerve activity can be identified through invasive recordings in awake humans. KEY POINTS: Intraneural recordings from the cervical vagus were obtained in awake humans via tungsten microelectrodes inserted into the nerve through ultrasound guidance. Cross-correlation analysis of multi-unit vagal activity revealed cardiac and respiratory modulation, from which the amplitude and latency of the peaks could be computed. The magnitude of the cardiac modulation (23%) was weaker than that of the respiratory modulation (45%). The latencies for the peak in cardiac modulation showed a bimodal distribution: the majority of sites (72%) had peak latencies that preceded the R-wave, while the remainder had latencies that followed the R-wave. The majority of sites with negative latencies (68%) were found in the left nerve whereas most of those with positive latencies (75%) were found in the right. On average the peak of respiratory modulation coincided with the peak of inspiration.

Screening-guided spironolactone treatment of subclinical left ventricular dysfunction for heart failure prevention in at-risk patients.

AIMS: Subclinical left ventricular dysfunction (LVD) is a prelude to symptomatic heart failure (HF). We hypothesised that screening-guided treatment with spironolactone would prevent incident HF in at-risk patients. METHODS AND RESULTS: We randomised asymptomatic, community-dwelling subjects aged ≥65 years old, with at least one non-ischaemic HF risk factor (hypertension, type 2 diabetes mellitus or obesity) to echocardiography-guided therapy or usual care. Spironolactone therapy was triggered by the detection of subclinical LVD (global longitudinal strain [GLS] ≤16%) or diastolic abnormalities (at least one of E/e' >15, E/e' >10 with left atrial enlargement [LAE] or impaired relaxation [E/A < 0.8, IR], LAE with IR), or borderline GLS (17%) with IR or borderline GLS with LAE. The primary outcome was incident HF at 24 months. Secondary outcomes were change in 6-min walk test (6MWT) and change in left ventricular function. LVD was identified in 161 (46%) of 349 participants (age 70 [68-73] years, 201 [58%] women). The trial was stopped because of a 55% rate of spironolactone discontinuation, due primarily to decline in renal function. Incident HF developed in 11 (3.5%) of 310 participants completing follow-up, with no difference between usual care and intervention (4 [2.5%] vs. 7 [4.7%], p = 0.29), decline in 6MWT distance (p = 0.28), persistent or new LVD (p = 0.58), nor change in GLS with intervention (p = 0.15). A per-protocol analysis of 131 patients with baseline LVD and a follow-up echocardiogram, showed resolution of LVD with spironolactone therapy (59% vs. 33%, p = 0.01). CONCLUSION: The study was underpowered to determine whether screening-guided spironolactone therapy reduced incident HF because spironolactone was frequently discontinued due to renal function criteria. However, LVD resolved in more patients treated with spironolactone than in untreated patients. Future trials should use less conservative renal criteria for spironolactone discontinuation.